Vinyl sulfonamide synthesis for irreversible tethering via a novel α-selenoether protection strategy

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Title: Vinyl sulfonamide synthesis for irreversible tethering via a novel α-selenoether protection strategy
Authors: Craven, G
Affron, D
Raymond, P
Mann, D
Armstrong, A
Item Type: Journal Article
Abstract: Vinyl sulfonamides are valuable electrophiles for targeted protein modification and inhibition. We describe a novel approach to the synthesis of terminal vinyl sulfonamides which uses mild oxidative conditions to induce elimination of an α-selenoether masking group. The method complements traditional synthetic approaches and typically yields vinyl sulfonamides in high purity after aqueous work-up without requiring column chromatography of the final electrophilic product. The methodology is applied to the synthesis of covalent fragments for use in irreversible protein tethering and crucially enables the attachment of diverse fragments to the vinyl sulfonamide warhead via a chemical linker. Using thymidylate synthase as a model system, ethylene glycol is identified as an effective linker for irreversible protein tethering.
Issue Date: 1-Jan-2019
Date of Acceptance: 11-Dec-2018
URI: http://hdl.handle.net/10044/1/66774
DOI: https://dx.doi.org/10.1039/C8MD00566D
ISSN: 2040-2503
Publisher: Royal Society of Chemistry
Start Page: 158
End Page: 163
Journal / Book Title: MedChemComm
Volume: 10
Copyright Statement: © The Royal Society of Chemistry 2019
Keywords: Science & Technology
Life Sciences & Biomedicine
Biochemistry & Molecular Biology
Chemistry, Medicinal
Pharmacology & Pharmacy
COVALENT INHIBITORS
DISCOVERY
DESIGN
REACTIVITY
FRAGMENTS
PROTEASE
KINASE
SITE
0304 Medicinal And Biomolecular Chemistry
0305 Organic Chemistry
1115 Pharmacology And Pharmaceutical Sciences
Publication Status: Published
Embargo Date: 2019-12-13
Online Publication Date: 2018-12-13
Appears in Collections:Chemistry
Faculty of Natural Sciences



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